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Biogen Idec and Elan Announce Head-to-Head Study Comparing Safety and Efficacy of TYSABRI® to Rebif®
Zug, Switzerland – December 21, 2004 – Biogen Idec and Elan announced today that they are initiating a head-to-head study comparing the safety and efficacy of TYSABRI® (natalizumab) to Rebif® (Interferon beta-1a)*. STARS (Study of TYSABRI Against Rebif in relapsing multiple Sclerosis), is a randomized, assessor-blinded, parallel group study that will enroll more than 1,000 multiple sclerosis (MS) patients in North and South America, Europe, Australia, Turkey and Israel.

Patients who enroll in the study will be randomized to either treatment on Rebif, administered subcutaneously at 44 mcg three times per week, or treatment with TYSABRI, administered as a 300 mg IV infusion once every four weeks. The primary endpoint will compare the effect of TYSABRI to Rebif on the rate of clinical relapses. Secondary endpoints include analysis of the proportion of patients remaining relapse free, MRI brain scans, safety, tolerability and quality of life. To help ensure the objectivity of data emerging from STARS, relapses will be assessed and determined in a blinded fashion by an independent panel of experienced neurologists who are not participants in the study. The companies expect to enroll the first patient in STARS in the first quarter of 2005.

“TYSABRI has shown very encouraging efficacy results and a favorable safety profile after one year, both as a monotherapy and as an add-on therapy to AVONEX® (Interferon beta-1a),” said Ludwig Kappos, MD, professor of neurology, Basel University, Switzerland, and member of STARS independent panel. “This head-to-head comparison with Rebif will provide important information that will further assist patients and physicians in making therapeutic choices.”

On November 23, 2004, TYSABRI became the first monoclonal antibody approved by the U.S. Food and Drug Administration (FDA) for the treatment of relapsing forms of MS. The FDA granted Accelerated Approval for TYSABRI following Priority Review based on one-year data from two ongoing Phase III studies, the AFFIRM monotherapy trial and the SENTINEL add-on trial with AVONEX. In the AFFIRM study, TYSABRI reduced the rate of relapses by 66 percent relative to placebo. In the SENTINEL study, the addition of TYSABRI to AVONEX resulted in a 54 percent reduction in the rate of clinical relapses over the effect of AVONEX alone.

Common adverse events associated with TYSABRI include headache, fatigue, urinary tract infection, depression, lower respiratory tract infection, joint pain and abdominal discomfort. The rate of infection in both studies was approximately one per patient-year in both TYSABRI-treated patients and placebo-treated patients. Serious infections occurred in 1.3 percent of placebo-treated patients and 2.1 percent of TYSABRI-treated patients. Serious infections included bacterial infections such as pneumonia and urinary tract infection, which responded appropriately to antibiotics. TYSABRI has been associated with hypersensitivity reactions, including serious systemic reactions, which occurred at an incidence of less than 1 percent of patients.

About TYSABRI

TYSABRI inhibits adhesion molecules on the surface of immune cells. Research suggests TYSABRI works by preventing immune cells from migrating from the bloodstream into the brain where they can cause inflammation and potentially damage nerve fibers and their insulation.

Biogen Idec and Elan are collaborating equally on the development of TYSABRI in MS, Crohn's disease and rheumatoid arthritis. Regulatory authorities in Canada and Australia have designated TYSABRI for Priority Review for the treatment of MS, and the European Medicines Agency (EMEA) is actively reviewing the application. To date, more than 2,800 patients have received TYSABRI in clinical trials.

The primary endpoint will compare the effect of TYSABRI to Rebif on the rate of clinical relapses. Secondary endpoints include analysis of the proportion of patients remaining relapse free, MRI brain scans, safety, tolerability and quality of life. To help ensure the objectivity of data emerging from STARS, relapses will be assessed and determined in a blinded fashion by an independent panel of experienced neurologists who are not participants in the study.

In other threads there's been discussion about how study results are hard to interpret because the definition of a relapse is subjective. This may be a step in the right direction.

dancingfish wrote:What is odd is our neurologist is ready to use Rebif and Tysbri right now..

Hmmm...the most powerful of the interferons that has the most side effects combined with a monoclonal antibody and there is no data on how this combination might work!! Don't think I would want to be the "guinea pig" in this situation.

Biogen Idec Inc. has set up what amounts to a clinical trial smackdown with archrival Serono Inc., testing the safety and efficacy of the Cambridge firm's new multiple sclerosis treatment, Tysabri, against the Swiss upstart's challenger, Rebif.

The purse: the global market to treat MS patients, expected to reach $6 billion within two years.

Tysabri, which Biogen developed with Dublin-based Elan Corp., won fast-track approval last month from the U.S. Food and Drug Administration.

The drug, which is delivered intravenously in a two-hour procedure every four weeks, is expected to replace Biogen's other MS med, Avonex, the current market leader.

But come next month, Biogen will begin enrolling more than 1,000 people with relapsing MS in a head-to-head study against Serono's Rebif, the overseas market leader.

``Rebif is a leading competitor internationally, so we decided to initiate this trial,'' said Biogen spokeswoman Amy Brockelman.

``We believe we have the new market leader in Tysabri,'' she said.

Not so fast, said Serono U.S.'s chief medical officer. ``The fact that they've chosen Rebif is a compliment,'' Paul Lammers said. ``We have the fastest growing disease-modifying drug in the U.S.''

But one New York analyst seemed to lay odds against Serono's Rebif of winning this head-to-head contest, the results of which will be made public in about two years, Biogen said.

HarryZ wrote:Hmmm...the most powerful of the interferons that has the most side effects combined with a monoclonal antibody and there is no data on how this combination might work!! Don't think I would want to be the "guinea pig" in this situation.Harry

Well, to be fair, they do have 1 year data on Avonex + Tysabri and it appears quite safe. It is unlikely Rebif will be much different.

They are using Avonex with Tysabri to show that interferons are safe and effective taken with Tysabri and using Rebif and Tysabri to show (presumably) that Tysabri is better than interferons. From a marketing perspective it will look much better if there is only data showing the benefits come with Avonex and the lesser effects come with Rebif - even though you could pretty much swap the two and expect the same results.
Sly marketing weenies strike again.

Well, to be fair, they do have 1 year data on Avonex + Tysabri and it appears quite safe. It is unlikely Rebif will be much different.

Rebif is a more potent interferon and is the one that is most capable of producing NAbs. According to the John Hopkins Tysabri webcast, 9% of the Tysabri users in the trial ended up having to stop the treatment due to high NABs that weren't going away after a number of months. Now combine the two...hmmm...don't think I would want to be taking them!

They are using Avonex with Tysabri to show that interferons are safe and effective taken with Tysabri and using Rebif and Tysabri to show (presumably) that Tysabri is better than interferons. From a marketing perspective it will look much better if there is only data showing the benefits come with Avonex and the lesser effects come with Rebif - even though you could pretty much swap the two and expect the same results.Sly marketing weenies strike again.

Why do I get the feeling that the potential for increased revenue is taking precedence over what is really better for the patient when it comes to combining these drugs. Like you said, very slick marketing and nobody is better at it than Biogen!

Rebif is a more potent interferon and is the one that is most capable of producing NAbs. According to the John Hopkins Tysabri webcast, 9% of the Tysabri users in the trial ended up having to stop the treatment due to high NABs that weren't going away after a number of months. Now combine the two...hmmm...don't think I would want to be taking them!

Actually, Betaseron has the highest incidence of NAbs (and the Tysabri product spec say 6% had NAbs to Tysabri), but I'm not sure what danger you are alluding to. NAbs *neutralize* the drug in question - making it ineffective. It's like not taking the drug. Nobody has reported a danger from this (other than financial).

With Tysabri they seem to know how to detect them and when they are likely to occur, so you can be taken off the drug and not waste your time/money using it if you are in the unlucky group.

As to the combination being worse, I'm having a hard time imagining how NAbs to one drug would have anything to do with the other given how utterly and completely different their structures are and how specific antibodies are.

Can you illucidate how your fears might manifest themselves? I can understand a general "this is a new compound, I wouldn't stick it in my body until more is known" (I'm sort of in that camp) but you seem to be hinting at something more specific.

I don't think we've seen any vendor specific drug interactions with the interferons so far. The NAbs differences seem to be due to route of administration and production quality, not dose level.

EDIT: I just checked - Tysabri NAbs appeared in 10% of subjects at least once with 6% having persistent NAbs.

Actually, Betaseron has the highest incidence of NAbs (and the Tysabri product spec say 6% had NAbs to Tysabri), but I'm not sure what danger you are alluding to. NAbs *neutralize* the drug in question - making it ineffective. It's like not taking the drug. Nobody has reported a danger from this (other than financial).

Yes, Betaseron does give high NABs but its use is slowly diminishing. The original data on Tysabri showed 6% got NABs but the webcase stated 9%.NABs can do a lot of damage to you other than just make your MS medication useless. They can wreck havoc with your immune system if left untreated. Many patients on the CRABs experience elevated NABs but most patients have the NABs return to normal after a period of time. Some people, however, have to be treated if they don't go down on their own.

With Tysabri they seem to know how to detect them and when they are likely to occur, so you can be taken off the drug and not waste your time/money using it if you are in the unlucky group.

That's because the docs were keeping a very close eye on them knowing that they could become elevated with the drug. I can't count the number of times I read about CRAB users whose docs never bothered to check them for NABs and would ask on the net what they were!!

As to the combination being worse, I'm having a hard time imagining how NAbs to one drug would have anything to do with the other given how utterly and completely different their structures are and how specific antibodies are.

That's the problem...very little is known about combining the drugs.

Can you illucidate how your fears might manifest themselves? I can understand a general "this is a new compound, I wouldn't stick it in my body until more is known" (I'm sort of in that camp) but you seem to be hinting at something more specific.

My additional concerns come from speaking with some knowledgeable people in MS medicine...docs, nurses and researchers. Some of these people are very uncomfortable with the speed that Tysabri got approved, especially using only one year data from the Phase III trial. These medical people are used to having a lot more data available for a new drug and so far that data simply isn't available. Everything that we have heard has come from Biogen and they don't have the greatest reputation in providing information to the medical community. I have heard that comment on more than one occasion. Who knows, maybe when all the data from the Phase III trials becomes published and then peer reviewed, these attitudes may change.

I don't think we've seen any vendor specific drug interactions with the interferons so far. The NAbs differences seem to be due to route of administration and production quality, not dose level.

Perhaps but there has to be a lot more research done in this area.

EDIT: I just checked - Tysabri NAbs appeared in 10% of subjects at least once with 6% having persistent NAbs.

Geez. it just went up 1% while reading your message You know, 6% is kind of a high level for persistency in one year data. It will interesting to see what the two year data gives us.

NABs can do a lot of damage to you other than just make your MS medication useless. They can wreck havoc with your immune system if left untreated. Many patients on the CRABs experience elevated NABs but most patients have the NABs return to normal after a period of time. Some people, however, have to be treated if they don't go down on their own.

I've never heard of this. Got any pointers or other info on it? What sort ot treatment do they get? I'd like to know more.

I've never heard of this. Got any pointers or other info on it? What sort ot treatment do they get? I'd like to know more.

Health Canada published some warnings on NAbs this past year...I'll have to do some searching to see if I can find the actual articles. I did manage to save one link (published by Biogen, who else?) who pointed out that their competitors' products produced more NAbs than did Avonex!

I've been using Google to search about elevated NABs in MS patients. Dozens and dozens of articles but most of them, like you stated, refer to the NABs effect on diminishing the effectiveness of an interferon and don't go beyond that. There were a couple of articles that indicated more info than this but they were part of journals that you had to subscribe to in order to read the publication.

I did manage to find the Health Canada Warning about serious possible liver damage when using the interferons. I can't be positive of what causes the elevated liver enyzmes in this situation...the NABs or something else.

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